Trial Title:
Proseq Cancer: Genomic Profiling in Patients With Incurable Cancer in Search for Targeted Treatment
NCT ID:
NCT05695638
Condition:
Solid Tumor, Unspecified, Adult
Haematological Malignancy
Conditions: Official terms:
Hematologic Neoplasms
Conditions: Keywords:
Precision medicine
Personalized medicine
Genomic profiling
Tissue agnostic
Study type:
Observational [Patient Registry]
Overall status:
Recruiting
Study design:
Time perspective:
Prospective
Summary:
Proseq Cancer is a precision medicine program based on in-house whole exome sequencing
(WES) and RNA sequencing. The approved protocol allows for biobanking, registration of
clinical and laboratory data, and sharing of genomic data with the purpose of research,
while fulfilling the Danish General Data Protection Regulation (GDPR) requirements.
Patients are recruited from the North Denmark Region.
Treatment can be offered on site if a targeted drug of a nationally approved indication
is suggested by the national tumor board (NTB). If not, the patient may be treated in an
available clinical protocol. If no approved drug or relevant protocol is available or
feasible, treatment with a targeted drug used outside a clinical protocol is pursued.
Detailed description:
Patients are recruited from the North Denmark Region. This is a precision medicine
program based on in-house whole exome sequencing (WES) and RNA sequencing (RNAseq). All
eligible patients are offered enrollment in an approved protocol, which allows for
biobanking, registration of clinical and laboratory data, and sharing of genomic data
with the purpose of research, while fulfilling the Danish GDPR requirements.
After informed consent clinical-pathological baseline data is registered by oncological
investigators. Results of new pathological and molecular assessments are prospectively
registered as well as decisions made at the National molecular Tumor Board (NTB).
New 1.2 mm core needle biopsies are taken from the most easily accessible, preferably
progressing tumor lesion that has not been irradiated, usually guided by ultrasound.
Biopsies from centrally located lung lesions or other sites with increased risk of
complications, or procedures requiring general anesthesia are generally avoided. In each
case, one biopsy is fixed in neutral-buffered formalin and allocated to histopathological
assessment. Another, adjacent 1-2 biopsies are kept in RNAlater until processing for
molecular analysis within 5 days. Patients with intracranial tumors are biopsied at time
of diagnostic surgery or if surgery is otherwise required, and tissue is kept frozen at
-80°C until the clinical course indicates that patients are eligible for the protocol. In
parallel, a 10 ml EDTA blood sample is drawn for analysis of non-tumoral DNA. Unfixed or
fresh frozen tissue material is preferred. However, in selected patients for whom a new
biopsy is unobtainable and no fresh frozen tissue is available, DNA is extracted from the
most recent FFPE archival sample of tumor tissue. Cell-free tumor-DNA (ctDNA) from
peripheral blood samples is used in cases with insufficient tissue for analysis. Samples
for ctDNA analysis are collected in cell-free DNA blood collection tubes (Streck).
The FFPE tumor biopsies are cut into four sections of 4 µm and one of 1 µm. One 4 µm
section is stained with hematoxylin and eosin and another with HER2-antibody. The cancer
and histological subtype are diagnosed by senior consultant pathologists. Additional
pathological analyses, including immunohistochemistry or targeted NGS, are done on FFPE
tissue at the initiative of the pathologist, or if requested by investigators or the
tumor board.
The molecular profiling is performed in-house, but may also be performed at other sites.
The in house procedure is as follows: Tissue biopsies in RNAlater or fresh frozen tissue
are homogenized, and RNA and DNA is extracted using Qiagen AllPrep®. Non-tumoral DNA for
profiling is extracted from peripheral blood leukocytes using QiaSymphony DSP DNA midi
kit (Qiagen). WES library preparation is performed using the Sureselect XT HS Library
Prep Kits (Agilent). Exome capture is performed using the SureSelect XT HS Clinical
Research Exome V2 (Agilent), while RNAseq library preparation is done using the TruSeq
Stranded mRNA Library Prep Kit (Illumina). Sequencing is carried out as 2x150 bp
paired-end on a NovaSeq 6000 (Illumina), producing minimum 26 Gb, 18 Gb, or 33 million
reads of raw sequence data for tumor DNA, non-tumoral DNA, or tumor RNA samples,
respectively. For molecular profiling the tumor DNA is subjected to somatic short variant
detection using tumor/normal WES analysis, detection of copy number alterations, TMB and
MSI status, and mutational signature analysis. Tumor RNA is used for the generation of an
expression profile used as input for tissue classification26. Moreover, RNAseq enables
detection of fusion transcripts for identification of larger chromosomal abbreviations.
ctDNA is extracted from 10 ml blood samples or, in few cases, from peritoneal fluid in
cell-free DNA blood collection tubes (Streck) using QiaSymphony Virus/pathogen Midi Kit
(Qiagen). TruSight Oncology 500 assay (Illumina) is used for library preparation. 2x150
bp paired-end sequencing is performed on a NovaSeq 6000 (Illumina) producing minimum
1500x coverage of the targeted regions.Using the non-tumoral DNA, clinically relevant
pathogenic variants are detected in a small set of genes (BRCA1, BRCA2, ATM, MLH1, MSH2,
MSH3, PMS1, MLH3, MSH6, PMS2, PALB2, RAD51C, RAD51D, MBD4, ANKRD26, CEBPA, DDX41, ETV6,
GATA3, RUNX1, TERC, TERT and TP53). Germline variants in other genes are not analyzed,
unless specifically requested by clinical geneticists and consented by the patient. Raw
sequencing data are processed and stored under the regional IT-system. Sequencing data
and supplementary metadata are submitted to the Danish National Genome Center. The in
house bioinformatic procedure is as follows: Using Genome Analysis Tool Kit (GATK) the
process largely follows the GATK-recommendations. The filtered variant file (VCF) is
uploaded together with information on sex, age, diagnosis and detected fusion
transcripts, gene losses or gains, to Qiagen Clinical Insight Interpret (QCI) for
automatic classification of variants. All variants of clinical significance are manually
verified by visual inspection of the DNA and RNAseq data. Variants are classified as
pathogenic, likely pathogenic, variants of unknown significance (VUS), or benign/likely
benign. QCI is also used prospectively to link variants and approved treatments or
clinical trials into tiers. Non-tumoral variants are classified according to the 2015
ACMG/AMP guidelines and are, together with the history of patients, reviewed by an MD
specialized in clinical genetics. If a germline variant with a likely consequence for the
health of the patient or a relative is identified, patients who had requested this
information at protocol consent are offered referral to the Department of Clinical
Genetics. Reports are generated using a dedicated platform (PrOnco) from clinical data
stored in REDCap and variants data. The platform enables a tumor board report to be
generated on demand or made accessible through an interactive interface.
Cases are presented at a weekly web-based multidisciplinary NTB, directed by the phase I
unit at Rigshospitalet, Copenhagen. Based on patients' history and characteristics,
disclosed molecular variants, gene signatures or other tumor characteristics and
available trials or drugs, matched treatments and early phase clinical trials are
suggested.
Treatment can be offered on site if a targeted drug of a nationally approved indication
is suggested by the NTB. If not, the patient may be treated in an available clinical
protocol. This especially includes the ProTarget trial - a nation-wide,
investigator-initiated basket trial of targeted treatment, studying the efficacy of
approved drugs used "off label" in cohorts of patients with a similar target, similar
drug and similar diagnosis (NCT04341181). If no approved drug or relevant protocol is
available or feasible, treatment with a targeted drug used outside a clinical protocol is
pursued. This includes treatment with a drug that is labelled but not approved by the
Danish authorities, however, may be used after individual permission. It also includes
"off label" treatment after individual permission, or "compassionate use" with an
unapproved drug in a "named user program". Patients treated with matched targeted drugs
outside a clinical drug trial are evaluated by CT- or MR-scans and biomarkers at baseline
and every 8th or 9th week until progression. Blood samples for research are drawn and
stored in Bio-and Genome Bank Denmark, while treatment data is registered prospectively.
Criteria for eligibility:
Study pop:
Patients with incurable, progressing and/or life-threatening cancer with an expected
residual survival of at least 3 months and no efficient remaining standard treatment
options. Patients are recruited from the Region of Northern Jutland, Denmark.
Sampling method:
Non-Probability Sample
Criteria:
Inclusion Criteria:
- Incurable, progressing and/or life-threatening cancer
- Expected residual survival of at least 3 months
- No efficient remaining standard treatment options
- Patient recruited from the Region of Northern Jutland, Denmark
Exclusion Criteria:
- WHO Performance Status >2
- Significant comorbidity, concurrent medication or laboratory values imposing an
unacceptable risk at medical oncological treatment
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Department of Oncology, Aalborg University Hospital
Address:
City:
Aalborg
Zip:
9000
Country:
Denmark
Status:
Recruiting
Contact:
Last name:
Morten Ladekarl, MD, DMSci
Phone:
+45 97660545
Email:
morten.ladekarl@rn.dk
Contact backup:
Last name:
Anja Pagh, MD, PhD
Phone:
+45 97661417
Email:
a.pagh@rn.dk
Start date:
July 1, 2020
Completion date:
May 31, 2035
Lead sponsor:
Agency:
Morten Ladekarl
Agency class:
Other
Source:
Aalborg University Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05695638
